Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia a

Inclusion Criteria:

Study population will include: adult males >18 years of age with a diagnosis of severe hemophilia A and currently active or a history of FVIII inhibitors (≥0.6 BU). Females will be excluded because hemophilia A is an X-linked disorder that is extremely rare in females.

1. Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C by aone-stage PTT-based assay and coatest chromogenic factor VIII assay. Subjects withcurrently active or a history of positive FVIII inhibitor titers (≥0.6 BU)irrespective of their titer or current inhibitor status will be included forenrollment.

2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents orfactor VIII mimetics prior to referral for inclusion in the study.

3. Subjects who are treated on demand using factor VIII bypassing agents must have ahistory of four or more bleeding episodes requiring treatment in the six-monthperiod prior to referral for inclusion in the study.

4. Adequate bone marrow reserve as demonstrated by ANC >1.5/cu.mm; Hemoglobin >9g/dL;Platelets >100,000/microliter.

5. Adequate renal function, defined as creatinine clearance>60 ml/min (Cockroft-Gaultformula)

6. Adequate liver function, defined as defined as total bilirubin ≤1.5 times the upperlimit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3 times ULNat the time of screening, and no clinical signs or known laboratory/radiographicevidence consistent with cirrhosis.

7. Subject must sign an informed consent after explanation of the study and havingquestions answered.

8. Subject must be willing and able to document type of bleeding episodes and treatmentin a paper or electronic diary during the study.

9. Subject must be willing to return for regular follow-up visits during the 15-yearstudy.

Exclusion Criteria:

• A potential subject who meets any of the following exclusion criteria is ineligibleto participate in the study.

1. Therapy with factor VIII with the intent of immune tolerance induction within 30 days prior to inclusion within the study.

2. Enrollment in another interventional clinical trial within 60 days prior tostudy inclusion.

3. Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSCapheresis procedure or conditioning regimen.

4. Medically significant organ dysfunction that would prevent compliance withconditioning or would severely limit the probability of survival based onclinical status.

5. Those with a known co-existing clinically significant thrombophilic disorder,or as determined by the presence of any of the below identified on screeninglaboratory assessments:

• FV Leiden
• Protein S deficiency
• Protein C deficiency
• Prothrombin mutation (G20210A)
• D-dimer >3 x the upper limit of normal (ULN) at Screening All knownpatients with the above and any patient with a personal or significantfamily history of thrombotic events (DVT, PE, arterial clots) as deemed bythe principal investigator will be screened for the above disorders.

6. Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ arenot excluded).

7. Known bone marrow disorders or abnormal bone marrow cytogenetics.

8. Fertile males who are unwilling to use contraceptive techniques during and forthe twelve months following treatment.

9. Life expectancy severely limited by disease(s) other than hemophilia A.

10. Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT > 3 times theupper limit of normal).

11. Other active infectious disease that is a contraindicat ion forimmunosuppressive therapy.

12. Patients who have elective surgery scheduled during the study period.